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Martin J Bishop - One of the best experts on this subject based on the ideXlab platform.
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ventricular endocardial tissue geometry affects stimulus threshold and Effective Refractory Period
Biophysical Journal, 2018Co-Authors: Adam Connolly, Allen Kelly, Fernando O Campos, Rachel C Myles, Godfrey L Smith, Martin J BishopAbstract:Abstract Background: Understanding the biophysical processes by which electrical stimuli applied to cardiac tissue may result in local activation is important in both the experimental and clinical electrophysiology laboratory environments, as well as for gaining a more in-depth knowledge of the mechanisms of focal-trigger-induced arrhythmias. Previous computational models have predicted that local myocardial tissue architecture alone may significantly modulate tissue excitability, affecting both the local stimulus current required to excite the tissue and the local Effective Refractory Period (ERP). In this work, we present experimental validation of this structural modulation of local tissue excitability on the endocardial tissue surface, use computational models to provide mechanistic understanding of this phenomena in relation to localized changes in electrotonic loading, and demonstrate its implications for the capture of afterdepolarizations. Methods and Results: Experiments on rabbit ventricular wedge preparations showed that endocardial ridges (surfaces of negative mean curvature) had a stimulus capture threshold that was 0.21 ± 0.03 V less than endocardial grooves (surfaces of positive mean curvature) for pairwise comparison (24% reduction, corresponding to 56.2 ± 6.4% of the energy). When stimulated at the minimal stimulus strength for capture, ridge locations showed a shorter ERP than grooves (n = 6, mean pairwise difference 7.4 ± 4.2 ms). When each site was stimulated with identical-strength stimuli, the difference in ERP was further increased (mean pairwise difference 15.8 ± 5.3 ms). Computational bidomain models of highly idealized cylindrical endocardial structures qualitatively agreed with these findings, showing that such changes in excitability are driven by structural modulation in electrotonic loading, quantifying this relationship as a function of surface curvature. Simulations further showed that capture of delayed afterdepolarizations was more likely in trabecular ridges than grooves, driven by this difference in loading. Conclusions: We have demonstrated experimentally and explained mechanistically in computer simulations that the ability to capture tissue on the endocardial surface depends upon the local tissue architecture. These findings have important implications for deepening our understanding of excitability differences related to anatomical structure during stimulus application that may have important applications in the translation of novel experimental optogenetics pacing strategies. The uncovered preferential vulnerability to capture of afterdepolarizations of endocardial ridges, compared to grooves, provides important insight for understanding the mechanisms of focal-trigger-induced arrhythmias.
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modulation of Effective Refractory Period at the infarct border zone provides a mechanism for focal arrhythmogenesis
Computing in Cardiology Conference, 2016Co-Authors: Adam Connolly, Gernot Plank, Pawel Gawenda, Martin J BishopAbstract:Border-zone (BZ) tissue, representing viable yet re-modelled myocardium surrounding infarct scars, has been strongly correlated with arrhythmogenic risk post-myocardial infarction. How the electrophysiological re-modelling in BZ tissue facilitates arrhythmogenesis, particularly of a focal origin, is currently unknown. In this study, we used computational models of human ventricular tissue to quantify spatial changes in action potential duration (APD) and Effective Refractory Period (ERP) in the presence of electrophysiological BZ remodelling. Reductions in sodium channel conductivity to 35% increased ERP by > 30 ms relative to healthy tissue in absence of significant changes in APD due to a decrease in tissue excitability. When combined with re-modelling of re-polarising potassium currents, larger changes in ERP of > 60 ms occurred, due to concurrent increases in APD. Spatial plots of ERP along interfaces between healthy and BZ regions showed high spatial ERP gradients. Such heterogeneity may facilitate unidirectional block of nearby focal ectopic beats, providing an important focal arrhythmogenenic substrate.
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Structural Heterogeneity Modulates Effective Refractory Period: A Mechanism of Focal Arrhythmia Initiation
2016Co-Authors: Martin J Bishop, Adam Connolly, Gernot PlankAbstract:Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and Effective Refractory Periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium (72:6 vs 220:4 mA/cm2), with faster maximum AP upstroke velocities (257:3 vs 147:3 mV/ms), although noticeably very similar APDs (167:7 vs 168:4 ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to 40 ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most Effective induction sites were within channels of low ERPs between large vessels and epicardium. Significan
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local gradients in electrotonic loading modulate the local Effective Refractory Period implications for arrhythmogenesis in the infarct border zone
IEEE Transactions on Biomedical Engineering, 2015Co-Authors: Adam Connolly, Mark L Trew, Bruce H Smaill, Gernot Plank, Martin J BishopAbstract:Ectopic electrical activity that originates in the peri-infarct region can give rise to potentially lethal re-entrant arrhythmias. The spatial variation in electrotonic loading that results from structural remodelling in the infarct border zone may increase the probability that focal activity will trigger electrical capture, but this has not previously been investigated systematically. This study uses in-silico experiments to examine the structural modulation of Effective Refractory Period on ectopic beat capture. Informed by 3-D reconstructions of myocyte organization in the infarct border zone, a region of rapid tissue expansion is abstracted to an idealized representation. A novel metric is introduced that defines the local electrotonic loading as a function of passive tissue properties and boundary conditions. The Effective Refractory Period correlates closely with local electrotonic loading, while the action potential duration, conduction, and upstroke velocity reduce in regions of increasing electrotonic load. In the presence of focal ectopic stimuli, spatial variation in Effective Refractory Period can cause unidirectional conduction block providing a substrate for reentrant arrhythmias. Consequently, based on the observed results, a possible novel mechanism for arrhythmogenesis in the infarct border zone is proposed.
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structural heterogeneity modulates Effective Refractory Period a mechanism of focal arrhythmia initiation
PLOS ONE, 2014Co-Authors: Martin J Bishop, Adam Connolly, Gernot PlankAbstract:Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and Effective Refractory Periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium ( vs A/cm2), with faster maximum AP upstroke velocities ( vs mV/ms), although noticeably very similar APDs ( vs ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most Effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy.
Stuart M Cobbe - One of the best experts on this subject based on the ideXlab platform.
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effects of the class iii antiarrhythmic drug dofetilide on ventricular monophasic action potential duration and qt interval dispersion in stable angina pectoris
American Journal of Cardiology, 1992Co-Authors: Martin L Sedgwick, Henrik S Rasmussen, Stuart M CobbeAbstract:Abstract The effects of intravenous dofetilide on ventricular monophasic action potential duration and Effective Refractory Period at the right ventricular apex and outflow tract were studied in 18 patients (aged 37 to 70 years) with ischemic heart disease. Six patients received low-dose dofetilide as a 3 μg/kg loading dose over 15 minutes and a 1.5 μg/kg maintenance dose over 45 minutes; 6 received high-dose dofetilide 6 + 3 μg/kg and 6 placebo. During atrial pacing at a cycle length of 800 ms high-dose dofetilide prolonged right ventricular apex monophasic action potential duration by 45 ms (16%) and the Effective Refractory Period by 40 ms (16%). At the right ventricular outflow tract, monophasic action potential duration was prolonged by 45 ms (15%) and Effective Refractory Period by 55 ms (21%). During atrial pacing at a cycle length of 500 ms high-dose dofetilide prolonged the right ventricular apex monophasic action potential duration by 40 ms (18%) and the Effective Refractory Period by 43 ms (21%). The right ventricular outflow tract monophasic action potential duration was prolonged by 33 ms (14%) and Effective Refractory Period by 45 ms (21%). Dofetilide produced no increase in the dispersion of repolarization between the 2 sites. During the maintenance infusion QTc prolongation by highdose dofetilide averaged 43 ms (10%) with no increase of interlead QT dispersion. The effects of dofetilide on QT interval and Effective Refractory Period are shown to be due to a direct effect on action potential duration with no effect on dispersion. No rate dependence of monophasic action potential prolongation was detected at these cycle lengths.
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clinical and electrophysiologic effects of intravenous dofetilide uk 68 798 a new class iii antiarrhythmic drug in patients with angina pectoris
American Journal of Cardiology, 1992Co-Authors: Martin L Sedgwick, Henrik S Rasmussen, Stuart M CobbeAbstract:Dofetilide (UK-68,798) is a new class III antiarrhythmic agent. In animal experiments it selectively prolongs the Refractory Periods parallel to the action potential duration without any influence on upstroke velocity or conduction parameters. The present double-blind, placebo-controlled study was designed to show the effect of dofetilide on basic electrophysiologic parameters in patients with coronary artery disease. Eighteen patients (aged 31 to 64 years) with symptoms of stable angina pectoris admitted for routine coronary angiography were recruited. They were randomly allocated to receive either placebo or 1 of 2 dose levels of dofetilide intravenously with 6 patients in each group. Paired electrophysiologic variables were compared before and after administration of dofetilide. Both active dose levels produced significant prolongations (p less than 0.05) of 10 to 23% in atrial Effective Refractory Period, 6 to 16% in ventricular Effective Refractory Period and 11 to 15% in ventricular functional Refractory Period. Atrial functional Refractory Period was prolonged by 14 to 22% at the high-dose level (p less than 0.05). No effect was observed on conduction parameters (PA, AH, HV, PR or QRS intervals), sinus cycle length or sinus node recovery. The selective prolongation of the Refractory Periods in both atrium and ventricle, combined with a lack of effect on cardiac conduction parameters, indicates that this drug could be useful in the treatment of both atrial and ventricular reentrant tachyarrhythmias and fibrillation.
George F Van Hare - One of the best experts on this subject based on the ideXlab platform.
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atrioventricular nodal reentrant tachycardia in children effect of slow pathway ablation on fast pathway function
Journal of Cardiovascular Electrophysiology, 2002Co-Authors: George F Van Hare, Nancy A Chiesa, Robert M Campbell, Ronald J Kanter, Frank CecchinAbstract:AV Nodal Reentry in Children. Introduction: Prior studies in adults have shown significant shortening of the fast pathway Effective Refractory Period after successful slow pathway ablation. As differences between adults and children exist in other characteristics of AV nodal reentrant tachycardia (AVNRT), we sought to characterize the effect of slow pathway ablation or modification in a multicenter study of pediatric patients. Methods and Results: Data from procedures in pediatric patients were gathered retrospectively from five institutions. Entry criteria were age <21 years, typical AVNRT inducible with/without isoproterenol infusion, and attempted slow pathway ablation or modification. Dual AV nodal pathways were defined as those with ≥50 msec jump in A2-H2 with a 10-msec decrease in A1-A2. Successful ablation was defined as elimination of AVNRT inducibility. A total of 159 patients (age 4.4 to 21 years, mean 13.1) were studied and had attempted slow pathway ablation. AVNRT was inducible in the baseline state in 74 (47%) of 159 patients and with isoproterenol in the remainder. Dual AV nodal pathways were noted in 98 (62%) of 159 patients in the baseline state. Ablation was successful in 154 (97%) of 159 patients. In patients with dual AV nodal pathways and successful slow pathway ablation, the mean fast pathway Effective Refractory Period was 343 ′ 68 msec before ablation and 263 ′ 64 msec after ablation. Mean decrease in the fast pathway Effective Refractory Period was 81 ′ 82 msec (P < 0.0001) and was not explained by changes in autonomic tone, as measured by changes in sinus cycle length during the ablation procedure. Electrophysiologic measurements were correlated with age. Fast pathway Effective Refractory Period was related to age both before (P = 0.0044) and after ablation (P < 0.0001). AV block cycle length was related to age both before (P = 0.0005) and after ablation (P < 0.0001). However, in dual AV nodal pathway patients, the magnitude of change in the fast pathway Effective Refractory Period after ablation was not related to age. Conclusion: Lack of clear dual AV node physiology is common in pediatric patients with inducible AVNRT (38%). Fast pathway Effective Refractory Period shortens substantially in response to slow pathway ablation. The magnitude of change is large compared with adult reports and is not completely explained by changes in autonomic tone. Prospective studies in children using autonomic blockade are needed.
S H Hohnloser - One of the best experts on this subject based on the ideXlab platform.
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risk of development of delayed atrioventricular block after slow pathway modification in patients with atrioventricular nodal reentrant tachycardia and a pre existing prolonged pr interval
European Heart Journal, 2001Co-Authors: Gerian Gronefeld, Birgit Bender, C Machura, S H HohnloserAbstract:Aims The objective of this prospective study was to assess risk factors for the development of atrioventricular block following slow pathway modification in patients with atrioventricular nodal reentrant tachycardia and a pre-existing prolonged PR interval. Methods and Results Of 346 consecutive patients with atrioventricular nodal reentrant tachycardia undergoing slow pathway modification, 18 patients (62±7 years; five females) were found to have a prolonged PR interval prior to ablation. Total elimination of the functional slow pathway was assumed if the antegrade Effective Refractory Period following slow pathway modification was longer than the cycle length of atrioventricular nodal reentrant tachycardia. To detect atrioventricular node conduction disturbances, 24-h Holter recordings were performed 1 day prior to slow pathway modification, and 1 day, 1 week, 1, 3 and 6 months after the procedure. Six patients developed late atrioventricular block. The incidence of delayed atrioventricular block following successful slow pathway modification was higher in patients with, compared to patients without, prolonged PR interval at baseline (6/18 vs 0/328, P <0·001). In the former group, the antegrade Effective Refractory Period was longer in patients with, compared to those without, a delayed atrioventricular block (492±150ms vs 332±101ms, P <0·05). The incidence of delayed atrioventricular block was higher in patients with total elimination of the slow pathway compared to patients without (5/7 vs 1/11, P <0·01). Conclusions Slow pathway modification in patients with atrioventricular nodal reentrant tachycardia and a prolonged PR interval is highly Effective. However, there is a significant risk of development of delayed atrioventricular block, particularly when the procedure results in total elimination of the slow pathway.
Adam Connolly - One of the best experts on this subject based on the ideXlab platform.
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ventricular endocardial tissue geometry affects stimulus threshold and Effective Refractory Period
Biophysical Journal, 2018Co-Authors: Adam Connolly, Allen Kelly, Fernando O Campos, Rachel C Myles, Godfrey L Smith, Martin J BishopAbstract:Abstract Background: Understanding the biophysical processes by which electrical stimuli applied to cardiac tissue may result in local activation is important in both the experimental and clinical electrophysiology laboratory environments, as well as for gaining a more in-depth knowledge of the mechanisms of focal-trigger-induced arrhythmias. Previous computational models have predicted that local myocardial tissue architecture alone may significantly modulate tissue excitability, affecting both the local stimulus current required to excite the tissue and the local Effective Refractory Period (ERP). In this work, we present experimental validation of this structural modulation of local tissue excitability on the endocardial tissue surface, use computational models to provide mechanistic understanding of this phenomena in relation to localized changes in electrotonic loading, and demonstrate its implications for the capture of afterdepolarizations. Methods and Results: Experiments on rabbit ventricular wedge preparations showed that endocardial ridges (surfaces of negative mean curvature) had a stimulus capture threshold that was 0.21 ± 0.03 V less than endocardial grooves (surfaces of positive mean curvature) for pairwise comparison (24% reduction, corresponding to 56.2 ± 6.4% of the energy). When stimulated at the minimal stimulus strength for capture, ridge locations showed a shorter ERP than grooves (n = 6, mean pairwise difference 7.4 ± 4.2 ms). When each site was stimulated with identical-strength stimuli, the difference in ERP was further increased (mean pairwise difference 15.8 ± 5.3 ms). Computational bidomain models of highly idealized cylindrical endocardial structures qualitatively agreed with these findings, showing that such changes in excitability are driven by structural modulation in electrotonic loading, quantifying this relationship as a function of surface curvature. Simulations further showed that capture of delayed afterdepolarizations was more likely in trabecular ridges than grooves, driven by this difference in loading. Conclusions: We have demonstrated experimentally and explained mechanistically in computer simulations that the ability to capture tissue on the endocardial surface depends upon the local tissue architecture. These findings have important implications for deepening our understanding of excitability differences related to anatomical structure during stimulus application that may have important applications in the translation of novel experimental optogenetics pacing strategies. The uncovered preferential vulnerability to capture of afterdepolarizations of endocardial ridges, compared to grooves, provides important insight for understanding the mechanisms of focal-trigger-induced arrhythmias.
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modulation of Effective Refractory Period at the infarct border zone provides a mechanism for focal arrhythmogenesis
Computing in Cardiology Conference, 2016Co-Authors: Adam Connolly, Gernot Plank, Pawel Gawenda, Martin J BishopAbstract:Border-zone (BZ) tissue, representing viable yet re-modelled myocardium surrounding infarct scars, has been strongly correlated with arrhythmogenic risk post-myocardial infarction. How the electrophysiological re-modelling in BZ tissue facilitates arrhythmogenesis, particularly of a focal origin, is currently unknown. In this study, we used computational models of human ventricular tissue to quantify spatial changes in action potential duration (APD) and Effective Refractory Period (ERP) in the presence of electrophysiological BZ remodelling. Reductions in sodium channel conductivity to 35% increased ERP by > 30 ms relative to healthy tissue in absence of significant changes in APD due to a decrease in tissue excitability. When combined with re-modelling of re-polarising potassium currents, larger changes in ERP of > 60 ms occurred, due to concurrent increases in APD. Spatial plots of ERP along interfaces between healthy and BZ regions showed high spatial ERP gradients. Such heterogeneity may facilitate unidirectional block of nearby focal ectopic beats, providing an important focal arrhythmogenenic substrate.
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Structural Heterogeneity Modulates Effective Refractory Period: A Mechanism of Focal Arrhythmia Initiation
2016Co-Authors: Martin J Bishop, Adam Connolly, Gernot PlankAbstract:Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and Effective Refractory Periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium (72:6 vs 220:4 mA/cm2), with faster maximum AP upstroke velocities (257:3 vs 147:3 mV/ms), although noticeably very similar APDs (167:7 vs 168:4 ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to 40 ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most Effective induction sites were within channels of low ERPs between large vessels and epicardium. Significan
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local gradients in electrotonic loading modulate the local Effective Refractory Period implications for arrhythmogenesis in the infarct border zone
IEEE Transactions on Biomedical Engineering, 2015Co-Authors: Adam Connolly, Mark L Trew, Bruce H Smaill, Gernot Plank, Martin J BishopAbstract:Ectopic electrical activity that originates in the peri-infarct region can give rise to potentially lethal re-entrant arrhythmias. The spatial variation in electrotonic loading that results from structural remodelling in the infarct border zone may increase the probability that focal activity will trigger electrical capture, but this has not previously been investigated systematically. This study uses in-silico experiments to examine the structural modulation of Effective Refractory Period on ectopic beat capture. Informed by 3-D reconstructions of myocyte organization in the infarct border zone, a region of rapid tissue expansion is abstracted to an idealized representation. A novel metric is introduced that defines the local electrotonic loading as a function of passive tissue properties and boundary conditions. The Effective Refractory Period correlates closely with local electrotonic loading, while the action potential duration, conduction, and upstroke velocity reduce in regions of increasing electrotonic load. In the presence of focal ectopic stimuli, spatial variation in Effective Refractory Period can cause unidirectional conduction block providing a substrate for reentrant arrhythmias. Consequently, based on the observed results, a possible novel mechanism for arrhythmogenesis in the infarct border zone is proposed.
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structural heterogeneity modulates Effective Refractory Period a mechanism of focal arrhythmia initiation
PLOS ONE, 2014Co-Authors: Martin J Bishop, Adam Connolly, Gernot PlankAbstract:Reductions in electrotonic loading around regions of structural and electrophysiological heterogeneity may facilitate capture of focal triggered activity, initiating reentrant arrhythmias. How electrotonic loading, refractoriness and capture of focal ectopics depend upon the intricate nature of physiological structural anatomy, as well as pathological tissue remodelling, however, is not well understood. In this study, we performed computational bidomain simulations with anatomically-detailed models representing the rabbit left ventricle. We used these models to quantify the relationship between local structural anatomy and spatial heterogeneity in action potential (AP) characteristics, electrotonic currents and Effective Refractory Periods (ERPs) under pacing and restitution protocols. Regions surrounding vessel cavities, in addition to tissue surfaces, had significantly lower peak downstream electrotonic currents than well coupled myocardium ( vs A/cm2), with faster maximum AP upstroke velocities ( vs mV/ms), although noticeably very similar APDs ( vs ms) and AP restitution properties. Despite similarities in APDs, ERPs in regions of low electrotonic load in the vicinity of surfaces, intramural vessel cavities and endocardial structures were up to ms shorter compared to neighbouring well-coupled tissue, leading to regions of sharp ERP gradients. Consequently, focal extra-stimuli timed within this window of ERP heterogeneity between neighbouring regions readily induced uni-directional block, inducing reentry. Most Effective induction sites were within channels of low ERPs between large vessels and epicardium. Significant differences in ERP driven by reductions in electrotonic loading due to fine-scale physiological structural heterogeneity provides an important mechanism of capture of focal activity and reentry induction. Application to pathological ventricles, particularly myocardial infarction, will have important implications in anti-arrhythmia therapy.
